The proposed research seeks to elucidate the roles of various cells in the bone marrow (BM) microenvironment in the pathogenesis of multiple myeloma (MM), a once rare but increasingly more common hematologic malignancy that currently afflicts nearly 14,000 people in the U.S. each year. Despite treatment advances, MM remains incurable. The central hypothesis is that myeloma cells alter the cellular and cytokine milieu in the BM microenvironment to their growth and survival advantage. We will identify cellular elements critical for supporting the growth of MM, as well as other cell types that may restrain tumor growth. We recently developed the SCID-hu host system for primary human myeloma. In this in vivo system, primary myeloma cells grow exclusively in a human BM environment. As in patients, interaction of myeloma cells with the human BM microenvironment is associated with typical MM manifestations, providing an excellent tool for studying this interaction mechanism. In this study, we will concentrate on the role of osteoclasts and osteoblasts in the MM disease process. Our Specific Aims include the following: Specific Aim 1: Elucidate the reciprocal relationship between myeloma cells and osteoclasts. Myeloma cells induce osteoclastogenesis. We will test whether osteoclast activity is required for the growth of primary myeloma by treating myeloma-bearing SCID-hu hosts with osteoclast inhibitors. Using both in vitro and in vivo approaches, we will also test the ability of isolated osteoclasts to support myeloma growth. Specific Aim 2: Unravel the molecular mechanisms by which myeloma cells and osteoblasts affect each other. We hypothesize that osteoblasts produce factors that interfere with myeloma growth. We will test the ability of osteoblasts to affect the growth and survival of myeloma cells in vitro and in SCID-hu hosts. We will also test the effect of myeloma cells on the survival of osteoblasts in myelomatous bone, and examine the effect of these cells on the differentiation pathways of mesenchymal stem cells. By its conclusion, work under this study will have determined the importance of increased osteoclast activity to myeloma cell growth and survival, and whether interfering with myeloma-induced osteoclastogenesis will prevent and control MM. It will also have determined the involvement of osteoblasts in MM, and whether increasing bone formation in myelomatous bones will affect myeloma progression. This study will help develop an effective treatment for patients with MM or at risk of it, as well as its prevention.